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Review Article Disorders of Fluids and Electrolytes Julie R. Ingelfinger, M.D., Editor

Lactic Acidosis Jeffrey A. Kraut, M.D., and Nicolaos E. Madias, M.D.

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actic acidosis results from the accumulation of lactate and protons in the body fluids and is often associated with poor clinical outcomes. The effect of lactic acidosis is governed by its severity and the clinical context. Mortality is increased by a factor of nearly three when lactic acidosis accompanies low-flow states or sepsis,1 and the higher the lactate level, the worse the outcome.2 Although hyperlactatemia is often attributed to tissue hypoxia, it can result from other mechanisms. Control of the triggering conditions is the only effective means of treatment. However, advances in understanding its pathophysiological features and the factors causing cellular dysfunction in the condition could lead to new therapies. This overview of lactic acidosis emphasizes its pathophysiological aspects, as well as diagnosis and management. We confine our discussion to disorders associated with accumulation of the l optical isomer of lactate, which represent the vast majority of cases of lactic acidosis encountered clinically.

Pathoph ysiol o gic a l Fe at ur e s Normal Lactate Metabolism

The reaction integral to the generation or consumption of lactate is shown below:

From Medical and Research Services, Membrane Biology Laboratory, and the Division of Nephrology, David Geffen School of Medicine, University of California, Los Angeles, and the Veterans Affairs Greater Los Angeles Healthcare System — both in Los Angeles (J.A.K.); and the Department of Medicine, Division of Nephrology, St. Elizabeth’s Medical Center, and the Department of Medicine, Tufts University School of Medicine — both in Boston (N.E.M.). Address reprint requests to Dr. Kraut at the Division of Nephrology, VHAGLA Healthcare System, 11301 Wilshire Blvd., Los Angeles, CA 90073; or at j­kraut@​­ucla​.­edu; or to Dr. Madias at the Department of Medicine, St. Elizabeth’s Medical Center, 736 Cambridge St., Boston, MA 02135, or at ­nicolaos​.­madias@​­steward​.­org. N Engl J Med 2014;371:2309-19. DOI: 10.1056/NEJMra1309483 Copyright © 2014 Massachusetts Medical Society.

→ lactate + NAD+. pyruvate + NADH + H+ ← Pyruvate is generated largely by anaerobic glycolysis (Embden–Meyerhof pathway). The redox-coupled interconversion of pyruvate and lactate occurs in the cytosol and is catalyzed by lactate dehydrogenase (LDH), a tetramer with five isoforms, each made up of different combinations of two subunits, LDHA and LDHB.3 The LDHA subunit has a higher affinity for pyruvate and its reduction than does LDHB; thus, the nature of the LDH isoforms in tissues affects lactate metabolism. The blood lactate:pyruvate ratio is normally 10:1, but it rises with an increased ratio of NADH concentration ([NADH]) to NAD+ concentration ([NAD+]) (redox state).4 Approximately 20 mmol of lactate per kilogram of body weight is produced in the human body daily, primarily by highly glycolytic tissues containing LDHA-rich LDH, such as skeletal muscle.3,5 Lactate is reconverted to pyruvate and consumed in the mitochondria of the liver, kidney, and other tissues, which have LDHB-rich LDH. The pathways include the Cori cycle, which generates glucose but consumes ATP in the liver and kidney (gluconeogenesis), as well as the tricarboxylic acid cycle and oxidative phosphorylation in the liver, kidney, muscle, heart, brain, and other tissues, which generate ATP when pyruvate is oxidized to carbon dioxide and water. Lactate consumption is subserved by intraorgan and interorgan lactate shuttles facilitated by monocarboxylic acid transporters (MCTs), which mediate the influx and efflux of lactate and accompanying protons. Normally, the generation and consump-

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tion of lactate are equivalent, which results in a stable concentration of lactate in the blood.4,6 Lactate production can rise markedly, as exemplified by its increase by a factor of several hundred during maximal exercise,5 but it can also be rapidly consumed, as seen after cessation of exercise, seizures, or exogenous lactate loads.5,7 The bioenergetics of lactate generation can be summarized as follows: glucose + 2(ADP + inorganic phosphate) → 2 lactate + 2 H+ + 2 ATP. Production of lactate ions by means of glycolysis is accompanied by the release of an equivalent number of protons from the hydrolysis of the generated ATP. Conversely, lactate consumption removes an equivalent number of protons, thereby maintaining the internal acid–base balance.4 Hyperlactatemia

Hyperlactatemia occurs when lactate production exceeds lactate consumption. It also signifies the addition of a number of protons equivalent to the number of excess lactate ions, regardless of the prevailing acid–base status. Establishing the pathogenesis of hyperlactatemia can be a valuable guide to therapy. In tissue hypoxia, whether global or localized, lactate is overproduced and underutilized as a result of impaired mitochondrial oxidation (see Fig. S1A and S1B in the Supplementary Appendix, available with the full text of this article at NEJM .org).4 Even if systemic oxygen delivery is not low enough to cause generalized hypoxia, microcirculatory dysfunction can cause regional tissue hypoxia and hyperlactatemia.8 Coexisting acidemia contributes to decreased lactate removal by the liver; severe hypoxia and acidemia can convert the liver into a net lactate-producing organ.4 Hyperlactatemia can also result from aerobic glycolysis, a term denoting stimulated glycolysis that depends on factors other than tissue hypoxia. Activated in response to stress, aerobic glycolysis is an effective, albeit inefficient, mechanism for rapid generation of ATP. In the hyperdynamic stage of sepsis, epinephrine-dependent stimulation of the β2-adrenoceptor augments the glycolytic flux both directly and through enhancement of the sarcolemmal Na+,K+-ATPase (which consumes large quantities of ATP)9 (Fig. S1C in the

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Supplementary Appendix). Other disorders associated with elevated epinephrine levels, such as severe asthma (especially with overuse of β2-adrenergic agonists), extensive trauma, cardiogenic or hemorrhagic shock, and pheochromocytoma, can cause hyperlactatemia through this mechanism.9 In inflammatory states, aerobic glycolysis can also be driven by cytokine-dependent stimulation of cellular glucose uptake10; in alkalemic disorders, it can be driven by stimulation of 6-phosphofructokinase.4 Aerobic glycolysis and tissue hypoxia are not mutually exclusive; under certain circumstances, both can contribute to hyperlactatemia.4,9 Drugs that impair oxidative phosphorylation, such as antiretroviral agents and propofol, can augment lactic acid production and on rare occasions cause severe lactic acidosis. Patients receiving these drugs should be monitored carefully. The liver accounts for up to 70% of wholebody lactate clearance.11 In patients with sepsis, even when they are hemodynamically stable and have normal liver function, lactate clearance can be reduced, possibly through inhibition of pyruvate dehydrogenase.12 Chronic liver disease exacerbates hyperlactatemia due to sepsis or other disorders,7,11 but in the absence of such disorders, even severe cirrhosis rarely generates blood lactate levels that are more than minimally elevated. However, hyperlactatemia is common in acute fulminant liver disease, reflecting both reduced clearance and increased production of lactate by the liver,13 and is an important prognostic factor. Effects on Cellular Function

The cellular dysfunction in hyperlactatemia is complex. Tissue hypoxia, if present, is a major factor. If the cellular milieu is also severely acidic, cellular dysfunction is likely to be exacerbated. The latter factor alone can decrease cardiac contractility, cardiac output, blood pressure, and tissue perfusion; can sensitize the myocardium to cardiac arrhythmias; and can attenuate the cardiovascular responsiveness to catecholamines.14 In some studies, the severity of the acidemia was a better predictor of cellular dysfunction and clinical outcomes than the hyperlactatemia.15 However, acidemia is often absent as a result of coexisting acid–base disorders.7,14 The interaction of systemic acidity and blood lactate and their effect on clinical outcomes require further study.

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Lactic Acidosis

Whether hyperlactatemia itself has an effect on cellular function remains unclear. In vitro studies suggest that lactate can depress cardiac contractility,4,16 yet sodium lactate infusions that raised blood lactate to levels as high as 15 mmol per liter did not depress hemodynamic measures in patients after cardiac surgery.16

C ause s The major causes of lactic acidosis and their presumed mechanisms are listed in Table 1. Typically, they have been divided into disorders associated with tissue hypoxia (type A) and disorders in which tissue hypoxia is absent (type B). However, the evidence of tissue hypoxia can be subtle, and hyperlactatemia can be of both hypoxic and nonhypoxic origin.4,9,10 Cardiogenic or hypovolemic shock, severe heart failure, severe trauma, and sepsis are the most common causes of lactic acidosis, accounting for the vast majority of cases.17

Di agnosis Evidence of severe cardiopulmonary disease, the systemic inflammatory response syndrome, sepsis, severe trauma, or volume depletion offers important clues for diagnosing lactic acidosis. An elevated serum anion gap, particularly a value higher than 30 mmol per liter, can provide supportive evidence. However, other causes of a raised anion gap, such as ketoacidosis and toxic alcohol ingestion, should always be considered.18,19 The increase in the anion gap (ΔAG) can mirror the blood lactate level, but a close relationship might not always be found, since anions other than lactate often contribute to the ΔAG. A normal anion gap does not rule out lactic acidosis. In one study, 50% of patients with a serum lactate level of 5 to 10 mmol per liter did not have an elevated anion gap.18 Correction of the anion gap for the effect of serum albumin can improve its sensitivity, but many cases will still escape detection. Therefore, the serum anion gap lacks sufficient sensitivity or specificity to serve as a screening tool for lactic acidosis. Because a 1:1 relationship between the ΔAG and the decrease in serum bicarbonate concentration ([HCO3−]), ΔHCO3−, is often found in ketoacidosis, deviations from this ratio suggest coexist-

ing acid–base disturbances.19 In lactic acidosis, the ΔAG:ΔHCO3− ratio is often greater than 1, in part because the apparent space of distribution of protons exceeds that of lactate19,20; therefore, an increased ratio might not always suggest a coexisting acid–base disorder. An elevated blood lactate level is essential for confirmation of the diagnosis. The lower limit of the normal range for the blood lactate level, 0.5 mmol per liter, is consistent among clinical laboratories, but the upper limit can vary substantially, from as low as 1.0 mmol per liter to as high as 2.2 mmol per liter.6,21,22 Therefore, the cutoff for abnormal values often differs among laboratories. Levels at the upper tier of normal values have been associated with increased mortality among seriously ill patients.21,23 Thus, blood lactate concentrations at the upper tier of normal values or slightly increased from a previous baseline value, although remaining within the normal range, can augur a poor outcome and call for monitoring of the patient. Previously, the definition of lactic acidosis included a blood pH of 7.35 or lower and a serum [HCO3−] of 20 mmol per liter or lower.24 However, the absence of one or both of these features because of coexisting acid–base disorders does not rule out lactic acidosis. For example, coexisting respiratory alkalosis can increase the blood pH into the alkalemic range, whereas coexisting metabolic alkalosis can result in both hyperbicarbonatemia and alkalemia (Fig. 1 and 2). In contrast, coexisting respiratory acidosis can cause severe acidemia (Fig. 2). Lactic acidosis due to grand mal seizures is associated with normokalemia, because the concurrent entry of lactate and protons into cells negates the need for potassium exit from cells to maintain electroneutrality. However, hyperkalemia is commonly observed in critically ill patients, because they often have renal failure. In addition, potassium is released from damaged tissues. However, hypokalemia can occur when β2-adrenoceptor stimulation drives potassium into cells. A serum osmolal gap of more than 20 mOsm per kilogram of water has been reported in some cases,25 probably reflecting the release of osmotically active solute from ischemic tissues. However, other disorders characterized by an increased osmolal gap and hyperlactatemia (e.g., exposure to toxic alcohols) should be ruled out.

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Table 1. Causes of Lactic Acidosis.* Cause

Presumed Mechanism or Mechanisms

Cardiogenic or hypovolemic Decreased O2 delivery to tissues; epinephshock, advanced heart failure, rine-induced β2-adrenoceptor stimulaor severe trauma tion can be a contributory factor

Comments With sepsis, these causes account for the majority of cases of lactic acidosis

Sepsis

Epinephrine-induced β2-adrenoceptor stim- Evidence of decreased O2 delivery can be subtle; even in ulation with or without decreased O2 dethe absence of macrocirculatory impairment, dysfunclivery to tissues; reduced clearance of laction of microcirculation can be present tate even in hemodynamically stable patients

Severe hypoxemia

Decreased O2 delivery to tissues

Requires Pao2

Lactic acidosis.

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